1. Technical Field
This invention relates generally to a continuous antisolvent crystallization process for producing crystals with a narrow crystal size distribution, and relates more specifically to a continuous multistage plug flow crystallization system for the preparation of fine crystals of controlled size and crystal size distribution.
2. Background Art
Crystallization is one of the most widely used chemical processes in the world. Generally, crystallization is the process of forming solid crystals which precipitate from a solution or melt. More specifically, crystallization is comprised of two essential steps, nucleation and crystal growth. Crystallization from a solution begins with the nucleation of crystals followed by the growth of these nuclei to a finite size (i.e., crystal growth). Nucleation and growth follow separate kinetic regimes in which nucleation normally favors high driving forces (i.e., supersaturation) whereby growth favors low supersaturation. As the ratio of the rate of nucleation to growth during crystallization inevitably determines the crystal size distribution, higher supersaturation is preferred over lower supersaturation in order to produce smaller crystals. Attempts to produce crystals in the 1-5 μm range has led scholars to strive to produce methods that implement large supersaturations.
Previously known methods in the art for implementing large supersaturations are supercritical fluid crystallization, impinging jet crystallization, and spray drying. Each of the above-mentioned methods have significant drawbacks. For example, one such problem is the difficulty of substances that form organic molecular crystals to nucleate under high supersaturations, thus often producing amorphous material instead of desired crystals. A second problem is the difficulty to control, design and scale-up such processes resulting in a lack of commercial success. Moreover, undesired polymorphs may be produced in lieu of the desired crystalline compound given high levels of supersaturation. Further, polymorphs of organic molecular crystals are more susceptible to being produced because of the weak forces that hold molecules together in the lattice.
Polymorphism is defined as the ability of substances to crystallize into more than one distinct structure or polymorph. The distinct structures or polymorphs have different properties. These properties include density, shape, vapor pressure, solubility, dissolution rate, bioavailability, and electrical conductivity. Polymorphism is quite common among the elements of the Periodic Table as well as in organic and inorganic species.
When poor mixing is combined with high supersaturation, local zones with high variability of supersaturation are produced. In a batch process this can lead to uncontrolled crystallization with a wide crystal size distribution that is difficult to scale up or reproduce. A uniform supersaturation environment throughout the crystallizer is necessary to achieve desired particle size distributions that remain the same batch to batch in a batch vessel or achieve a steady state in a continuous vessel. Thus, mixing plays an important role in the size of crystals as well as the crystal size distribution, as intense and localized mixing on the micron and smaller scale helps to achieve more uniform supersaturation.
Well known mixing systems have been used to generate rapid mixing of solvent/antisolvent mixtures, and include mechanical stirrers, confined impinging jets, and tee mixers. Conventional chemical reactors make use of mechanical stirrers. Generally, a stirred tank reactor includes a vessel with baffles on the sides, wherein an impeller generates fluidic motion inside the vessel. The baffles prevent the fluid from circulating with the impeller. Confined impinging jets include two equal diameter fluid jet nozzles that collide streams of fluids within a small chamber, which subsequently are discharged though an outlet tube. Drawbacks to impinging jets include maintaining the alignment of the impinging fluid jet steams, difficult scale-up, and problems with clogging. Tee mixer devices include two opposed jets of equal diameter that collide and produce flow in an outlet tube. Similar to the impinging jet technology, tee mixers tend to clog easily. Thus, scale-up continues to be a challenge.
Another example of a mixer is a continuous pipe reactor with a static mixer therein, also referred to as a plug flow reactor. The static mixer is comparable to the impeller of a conventional chemical reactor. Static mixers have been used extensively in fields such as plastics, polymers and oil. Less information is readily known about the implementation of static mixers for producing pharmaceutical compounds. Static mixers consist of a series of elements of alternating clockwise and counterclockwise twist arranged axially within a tube to promote mixing. A key advantage of the static mixer over the impeller is the absence of moving parts. This results in lower maintenance and operating costs. Another advantage of a static mixer in a reactor is the absence of axial mixing. Axial mixing results in a broad residence time distribution. Because a narrow residence time distribution is necessary to produce a narrow particle size distribution, a continuous plug flow regime is preferred.
Crystallization also has long been recognized as an important process in the development of pharmaceutical compounds. In the pharmaceutical industry, over 90% of the active pharmaceutical ingredients (API) are crystals of small organic molecules. The method or process chosen to carry out crystallization directly affects the characteristics of pharmaceutical compounds such as crystal size distribution (CSD), crystal size, desired polymorphic transformation (i.e., crystal shape/habit), and purity. In relation to a crystal's polymorphic transformation tendencies, optimizing the crystallization process is essential to obtain crystals with high product quality and yield. Uniform yield is highly desirably for pharmaceutical companies when assessing their active ingredients for determining scale-up.
With regard to crystal size, it is generally known in the art that smaller crystals dissolve faster than larger crystals. In addition, smaller crystals tend to increase the speed of action and bioavailability of a pharmaceutical drug. Such characteristics are highly desirable for pharmaceutical companies seeking quick release of their active ingredients.
Thus, a need exists for an improved crystallization process and system to produce crystals having a narrow crystal size distribution, small crystal size, and high purity in the pharmaceutical industry. Further, a need exists for crystallization processes that produce consistent crystal size distributions, such that no batch to batch variations arise, or that achieve favorable steady state condition in continuous systems. Furthermore, a need exists for crystallization processes that are ideal for the pharmaceutical industry in view of scale-up considerations. It is to these needs and others that the present invention is directed.